HIV-1 is neurovirulent and can disrupt central nervous system (CNS) function. While combination antiretroviral therapy (ART) has sharply decreased incidence of the most severe manifestations of HIV neurovirulence (e.g., HIV-associated dementia), milder HIV-associated neurocognitive disturbances (HAND) continue to be observed in nearly half of patients, even in the context of successful viral suppression. As even this level of disability can undermine activities of daily living and threaten employment/self care independence, there is considerable research effort to identify and mitigate the physiologic mediators driving the pathogenesis of HAND. Current research areas include bolstering viral suppression in the brain with improved CNS penetration of ART, and attenuating direct neurotoxicity of drugs that do enter the CNS. However, all evidence indicates that etiology of HAND is complex and multi-factorial, and new and innovative ideas are needed to significantly advance this field. Many ART drugs can cause clinically severe metabolic co-morbidities, including lipodystrophy, dyslipidemia, and insulin resistance, but it is not known how such metabolic co-morbidities relate to HAND. However, numerous clinical studies have suggested enhanced prevalence and/or severity of neurologic complications in adult HIV patients with metabolic co-morbidities. Furthermore, recent manuscripts from our lab show that HIV ART drugs cause significant neurologic as well as metabolic dysfunction in mice, and suggest that lipodystrophy may be the critical physiologic mechanism linking metabolic to neurologic dysfunction. These data suggest therapies that prevent lipodystrophy and/or replicate adipocyte function in the face of lipodystrophy could provide novel and innovative therapies to preserve neurologic function in HIV patients. This R21 proposal will use novel experimental models to determine if adiponectin replacement therapy can preserve neurologic function in ART-treated mice, either through direct actions on the CNS, or by attenuating/preventing deterioration of metabolic function, or both. Specific Aim will test if the neurologic effects of ART are decreased in genetic mouse models of adiponectin overexpression, while Specific Aim 2 will test if pharmacologic ADP replacement therapy decreases the neurologic effects of ART in mice. Completion of these studies will reveal the therapeutic potential of adiponectin replacement therapy in ART-induced neurologic and metabolic function, and will thus also lead to a much better understanding of the degree to which, and the mechanisms by which ART-induced metabolic dysfunction could disrupt brain physiology and contribute to HIV neuropathogenesis.